Hepatitis C (HCV) is estimated to infect 4 million people in the United States and the prevalence in the African American (AA) population is estimated to be as high as 3%. Recently, a significant racial disparity in the response rate to therapy with Interferon and Ribavirin has been reported with only 5% of AA responding is compared to approximately 40% in the non AA population. The overall goal of the present proposal is to determine the etiology of this racial difference in response rates. We hypothesize that some combination of difference in the virus, interferon response or genetically determined factors such as immune response or receptors is responsible for this racial difference in response rates. The present proposal is designed to answer 4 specific questions: 1) Is there a difference in HCV quasispecies heterogeneity or selection either at baseline or in response to therapy 2) Are there differences in interferon sensitivity or response between races 3) Are there genetically determined differences in immune responses to HCV and 4) Are there allelic differences in CD81, a proposed receptor for HCV (and associated proteins, putative co-receptors). We will answer these questions by retrospectively and prospectively defining quasispecies heterogeneity in a treated AA cohort and comparing this to a Caucasian cohort. We will define differences in interferon sensitivity at the levels of interferon-receptor interaction, signal transduction and interferon-induced gene expression in these two cohorts. Immunological differences between cohorts will be evaluated by examining the differences in both strength and phenotype of T helper cell responses to HCV-specific and non-specific stimulation and also allelic differences in HLA and IL10 genotypes. Finally, we will analyze the genomic DNA of our cohorts for CD81 and look for allelic differences. We expect to see differences in any or all of these factors. Differences detected between cohorts will lead to an improved understanding of viral chronicity and will be applied to the development of improved therapies.